Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits
Pankratz, Nathan; Schick, Ursula M.; Zhou, Yi; Zhou, Wei; Ahluwalia, Tarunveer Singh; Allende, Maria Laura; Auer, Paul L.; Bork-Jensen, Jette; Brody, Jennifer A.; Chen, Ming Huei; Clavo, Vinna; Eicher, John D.; Grarup, Niels; Hagedorn, Elliott J.; Hu, Bella; Hunker, Kristina; Johnson, Andrew D.; Leusink, Maarten; Lu, Yingchang; Lyytikainen, Leo Pekka; Manichaikul, Ani; Marioni, Riccardo E.; Nalls, Mike A.; Pazoki, Raha; Smith, Albert Vernon; Van Rooij, Frank J A; Yang, Min Lee; Zhang, Xiaoling; Zhang, Yan; Asselbergs, Folkert W.; Boerwinkle, Eric; Borecki, Ingrid B.; Bottinger, Erwin P.; Cushman, Mary; De Bakker, Paul I W; Deary, Ian J.; Dong, Liguang; Feitosa, Mary F.; Floyd, James S.; Franceschini, Nora; Franco, Oscar H.; Garcia, Melissa E.; Grove, Megan L.; Gudnason, Vilmundur; Hansen, Torben; Harris, Tamara B.; Hofman, Albert; Jackson, Rebecca D.; Jia, Jia; Kahonen, Mika; Launer, Lenore J.; Lehtimaki, Terho; Liewald, David C.; Linneberg, Allan; Liu, Yongmei; Loos, Ruth J F; Nguyen, Vy M.; Numans, Mattijs E.; Pedersen, Oluf; Psaty, Bruce M.; Raitakari, Olli T.; Rich, Stephen S.; Rivadeneira, Fernando; Di Sant, Amanda M Rosa; Rotter, Jerome I.; Starr, John M.; Taylor, Kent D.; Thuesen, Betina Heinsbek; Tracy, Russell P.; Uitterlinden, Andre G.; Wang, Jiansong; Wang, Judy; Dehghan, Abbas; Huo, Yong; Adrienne Cupples, L.; Wilson, James G.; Proia, Richard L.; Zon, Leonard I.; O'Donnell, Christopher J.; Reiner, Alex P.; Ganesh, Santhi K.
(2016) Nature Genetics, volume 48, issue 8, pp. 867 - 876
(Article)
Abstract
Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. We analyzed erythrocyte and WBC phenotypes in 52,531 individuals (37,775 of European ancestry, 11,589 African Americans, and 3,167 Hispanic Americans) from 16 population-based cohorts with Illumina HumanExome BeadChip genotypes. We then performed replication analyses
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of new discoveries in 18,018 European-American women and 5,261 Han Chinese. We identified and replicated four new erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six new WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC count (MYB). The association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments for S1pr4 in mouse and s1pr4 in zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.
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Keywords: Genetics, Journal Article
ISSN: 1061-4036
Publisher: Nature Publishing Group
(Peer reviewed)